EP2756765B1 - Pharmaceutical compositions - Google Patents

Pharmaceutical compositions Download PDF

Info

Publication number
EP2756765B1
EP2756765B1 EP13151578.5A EP13151578A EP2756765B1 EP 2756765 B1 EP2756765 B1 EP 2756765B1 EP 13151578 A EP13151578 A EP 13151578A EP 2756765 B1 EP2756765 B1 EP 2756765B1
Authority
EP
European Patent Office
Prior art keywords
preparations
group
acid
glycosides
products
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP13151578.5A
Other languages
German (de)
French (fr)
Other versions
EP2756765A1 (en
Inventor
Veronika Somoza
Kathrin Ingrid Liszt
Elke Köck
Jakob Ley
Sabine Widder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Symrise AG
Original Assignee
Symrise AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Symrise AG filed Critical Symrise AG
Priority to EP13151578.5A priority Critical patent/EP2756765B1/en
Priority to PCT/EP2014/050742 priority patent/WO2014111436A1/en
Priority to US14/761,474 priority patent/US10226445B2/en
Priority to EP14702464.0A priority patent/EP2946208A1/en
Priority to PCT/EP2014/050950 priority patent/WO2014111546A1/en
Priority to US14/761,804 priority patent/US20150362481A1/en
Publication of EP2756765A1 publication Critical patent/EP2756765A1/en
Priority to US16/248,921 priority patent/US20190216770A1/en
Application granted granted Critical
Publication of EP2756765B1 publication Critical patent/EP2756765B1/en
Priority to US17/339,183 priority patent/US20210330641A1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F3/00—Tea; Tea substitutes; Preparations thereof
    • A23F3/40—Tea flavour; Tea oil; Flavouring of tea or tea extract
    • A23F3/405—Flavouring with flavours other than natural tea flavour or tea oil
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F5/00—Coffee; Coffee substitutes; Preparations thereof
    • A23F5/46—Coffee flavour; Coffee oil; Flavouring of coffee or coffee extract
    • A23F5/465—Flavouring with flavours other than natural coffee flavour or coffee oil
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/86—Addition of bitterness inhibitors
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the invention is in the field of pharmacy and foodstuffs and relates to preparations containing active ingredients against food constituent-induced secretion of gastric acid.
  • gastric acid secretion is an important mechanism for the initiation of digestion of food, especially protein-rich food dar. It may be quite positive for the digestion, the moderate additional short-term stimulation in addition. However, if gastric acid is excessively secreted by external stimuli and thus the pH in the stomach is lowered too much, this usually results, for example, acutely. to malaise or acid regurgitation. If this condition lasts longer or chronic gastric acid secretion is greatly stimulated, it can induce inflammatory conditions of the gastric mucosa and the esophagus, in turn, as ulceration late ulcer and in the worst case, even malignant tissue changes to gastric cancer and esophageal cancer.
  • Gastric acid secretion is induced in addition to the general stimuli such as food intake, starvation, etc., also by various low-molecular food components.
  • general stimuli such as food intake, starvation, etc.
  • various low-molecular food components For example, will from Liszt et al. in J. AGRIC FOOD CHEM. 60, 7022-7030 (2012 ) , that the fruit acids, malic acid and succinic acid, which are increasingly found in white wine, make a significant contribution to excessive acid secretion, which in the case of tartaric acid can be alleviated by alcohol.
  • hop ingredients can induce eg via beer consumption to a release of protons in the stomach contents (see. Walker et al. in J. AGRIC FOOD CHEM.
  • the object of the invention was therefore to find usable for or in food low molecular weight substances, preferably natural substances that are distinguished from the known active ingredients by better tolerability and higher performance and reduce the induced by the above food ingredients acid secretion or even completely prevent ,
  • a first subject of the invention relates to pharmaceutical preparations containing bitter-masking hydroxyflavanones selected from the group consisting of eriodictyol-7-methyl ether, homoeriodictyol, and their sodium, potassium, calcium, magnesium or zinc salts (component a) for use in reducing and / or inhibiting gastric acid secretion induced by food ingredients (component b), selected from the group formed by xanthine, fruit acids, phenolic glycosides, flavone glycosides, dihydrochalcone glycosides, hydrolyzable and nonhydrolyzable tannins and their oligomers, terpenoid or iridoid bitter substances and triterpene glycosides and mixtures thereof.
  • component b selected from the group formed by xanthine, fruit acids, phenolic glycosides, flavone glycosides, dihydrochalcone glycosides, hydrolyzable and nonhydrolyzable tannins and their oligomers, ter
  • substances which are able to mask the bitterness of many foods also simultaneously reduce or even inhibit the gastric acid secretion induced by these substances.
  • the substances of group (a) e.g. Homoeriodictyol, eriodictyol, matairesinol, lariciresinol or enterolactone the gastric acid stimulating effect of the substances of group (b), such. Caffeine or theobromine, in combination lower again or block completely.
  • bitter-masking agents constituting component (a) are, as mentioned, hydroxyflavanones, especially eriodictyol, eriodictyol-7-methyl ether, homoeriodictyol, and their salts of sodium, potassium, calcium, magnesium or zinc , especially such as those in the European patent application EP 1258200 A2 to be discribed.
  • the therapeutic preparations may contain both the components constituting components (a) and (b) in amounts of from about 0.1 mg / kg (corresponding to 0.1 ppm) to about 1% by weight.
  • the materials are each in amounts of from about 0.5 to about 1000 mg / kg (corresponding to about 0.5 to about 1000 ppm), preferably from about 1 to about 500 mg / kg, more preferably from about 3 to about 300 mg / kg, more preferably from about 5 to about 200 mg / kg, and most preferably from about 10 to 100 mg / kg.
  • compositions of the invention may comprise the materials which form components (a) and (b) in a weight ratio of from about 1: 100 to about 1: 1, preferably 1:90 to about 1: 2, and more preferably from about 1: 5 to about 1:10 included.
  • preparations are characterized in that they contain the component (a) and (b) respectively in amounts of 3 to 300 ppm.
  • Nutrition or pleasure (i.e., for human consumption) preparations are within the scope of this invention, e.g. Bakery products (eg bread, dry biscuits, cakes, other pastries), confectionery (eg chocolates, chocolate bar products, other bar products, fruit gums, hard and soft caramels, chewing gum), alcoholic or non-alcoholic drinks (eg coffee, tea, wine, wine-based drinks, Beer, beer-based drinks, liqueurs, schnapps, brandies, fruit-based sodas, isotonic drinks, soft drinks, nectars, fruit and vegetable juices, fruit or vegetable juice preparations), instant drinks (eg instant cocoa drinks, instant tea drinks, instant coffee drinks ), Meat products (eg ham, fresh sausage or raw sausage preparations, spiced or marinated fresh or salted meat products), eggs or egg products (dry egg, egg whites, egg yolk), cereal products (eg breakfast cereals, muesli bars, pre-cooked finished rice products), dairy products (eg milk drinks, Milk ice cream, yoghurt,
  • soy sauces eg jams, fruit ice cream, fruit sauces, fruit fillings
  • vegetable preparations eg ketchup, sauces, dried
  • the oral preparations according to the invention can also serve as semi-finished goods for the production of other orally consumable preparations.
  • the preparations according to the invention may also be in the form of capsules, tablets (oral and / or stomach-dissolving tablets), dragees, granules, pellets, solid mixtures, dispersions in liquid Phases, as emulsions, as powders, as solutions, as pastes or as other swallowable or chewable preparations as dietary supplements.
  • swallowable preparations eg drinks, dispersions, emulsions, pastes, in the mouth or stomach dissolvable capsules, tablets, compressed, soft caramel, dragees, Granules, pellets, fruit gums
  • non-swallowing preparations eg chewing gum, hard caramels
  • the substances of group (a) to be used according to the invention have no significant intrinsic taste in preparations according to the invention which are suitable for consumption, in particular they show no unpleasant or disturbing taste notes in the (preferred or particularly preferred) use concentrations.
  • the substances of group (a) alone and / or in mixture are able to reduce or completely block the bitterness of one or more of the substances of group (b).
  • the substance or substances of group (a) and preparations according to the invention containing the substance (s) of group (a) may be treated before, during or after oral intake of the substance (s) of group (b) or preparations containing the or the substances of group (b) are administered orally.
  • the substances of group (a) are regularly able to partially or completely reduce the bitter (unpleasant) taste of the substances of group (b) and thus significantly increase the acceptance of the preparations , This is especially the case if the substances of group (b) are applied simultaneously with substances of group (a).
  • preparation forms which contain the substance or substances of group (a) in a form which cause a delayed release are preferred.
  • preparations may also be suitable which having one or more of the unpleasant tasting and gastric acid stimulants of group (b) in an amount effective in gastric acid stimulation and simultaneously containing one or more of the substances of group (a) in an amount effective in gastric acid stimulation.
  • the oral preparations - be it finished or semi-finished products - both the substances that form the components (a) and (b), in amounts of about 0.1 mg / kg (corresponding to 0.1 ppm) to about 1 wt .-% included.
  • the substances are each in amounts of about 0.5 to about 1000 mg / kg (corresponding to about From about 1 to about 500 mg / kg, more preferably from about 3 to about 300 mg / kg, more preferably from about 5 to about 200 mg / kg, and most preferably about 10 to 100 mg / kg.
  • compositions of the invention may comprise the materials which form components (a) and (b) in a weight ratio of from about 1: 100 to about 1: 1, preferably 1:90 to about 1: 2, and more preferably from about 1: 5 to about 1:10 included.
  • a preferred method for determining the desired effect of substances of group (a) to reduce the effect of substances of group (b) is to measure the intracellular pH of human gastric tumor cell line (HGT-1) cell cultures after treatment with the test substances as in Liszt, AI; Walker, J .; Somoza, V. J. Agric. Food Chem. 2012, 60, (28), 7022-7030 described. So far, on the cell surface of gastric acid-secreting cells only the somatostatin receptor (SSTR2) has been described as a target for the reduction of secretion; this receptor has also been described in the HGT-1. So far, however, these cells have always only been brought into contact with potential SSTR2 regulators, co-administration of bitter agonists and potential antagonists has not previously been described.
  • SSTR2 somatostatin receptor
  • Human parietal cells also known as human gastric tumor cell line (HGT-1), are used as the cell model. These were from Dr. C. Laboisse (Laboratory of Pathological Anatomy, France ) made available. Cells are cultured under standard conditions 37 ° C, 5% CO 2 in DMEM (Dulbecco's Modified Eagle's Medium) with 4 g / L glucose, 10% FBS, 2% L-glutamine and 1% penicillin / streptomycin. For the measurement of the intracellular proton concentration, the cells are treated with trypsin / EDTA, the viability determined by tryptan blue staining and seeded 100,000 cells / well in black 96-well plates.
  • DMEM Dynamic Eagle's Medium
  • trypsin / EDTA the viability determined by tryptan blue staining and seeded 100,000 cells / well in black 96-well plates.
  • the dye 1.5 carboxy-seminaphtho-rhodafluoro acetoxymethyl ester (SNARF-1-AM) is used.
  • the cells in the 96-well plates are washed once with Krebs-Hepes buffer (KRHP) and incubated with the dye in the concentration of 3 ⁇ M dissolved in KRHP for 30 min at 37 ° C and 5% CO 2 .
  • the cells are washed twice with KRHP and with substances of group (b), for example 3 mM caffeine or 0.3 mM theobromine alone or in combination with substances of group (a), for example homoeriodictyol (HED) or eriodictyol or matairesinol, Lariciresinol or enterolactone in different concentrations in phenolrotrant DMEM volume of 100 ⁇ L applied; as a further control experiment, the abovementioned substances of group (a) alone are tested.
  • Homoeriodictyol is dissolved in double-distilled water while eriodictyol, matairesinol, lariciresinol or enterolactone are dissolved in ethanol (EtOH).
  • the final concentration of solvent supplied to the cells is at most 1%.
  • the fluorescent dye is excited at the wavelength of 488 nm and the emission is measured at 580 nm and 640 nm.
  • the ratio of the fluorescence values from 580 nm to 640 nm is plotted in comparison to the calibration curve, from which the pH value can be determined.
  • the cells are treated with a potassium buffer of pH 7.2 - 8.2 pH and 2 ⁇ M Nigericin. Nigericin equilibrates the intracellular and extracellular pH so that the intracellular pH can be defined.
  • the intracellular H + concentration is determined from the intracellular pH.
  • the intracellular proton index (IPX) is calculated by log2 transformation of the ratio between treated cells and untreated cells (control).
  • Table 1 B shows the percentage increase in proton secretion in HGT-1 cells compared to untreated controls after 10 minutes of stimulation by DMEM or DMEM with ETOH 1% or 1 mM histamine or 0.3 mM theobromine with and without EtOH 1%.
  • the drinking water is placed in a container and the maltodextrin and gum arabic dissolved therein. Subsequently, the substances of group (a) are emulsified with a Turrax in the carrier solution. The temperature of the spray solution should not exceed 30 ° C. The mixture is then spray-dried (nominal temperature input: 185-195 ° C, target temperature output: 70-75 ° C). The spray-dried semi-finished product contains about 18 - 22% of the compounds of group (a).
  • the compounds of group (a) were each pre-dissolved in ethanol at 10%.
  • Black tea extract was dissolved in water and stirred together with sugar, a flavoring preparation (peach flavor), and the ethanolic solutions of the compounds of group (a) in a beaker.
  • Citric acid (crystalline) 1.2 ascorbic acid 0.2 Homoeriodictyol in ethanol (10%) 0.05
  • the ready-to-consume gelatin capsules were prepared according to WO 2004/050069 and had a diameter of 5 mm, the weight ratio of core material to shell material was 90:10.
  • the capsules opened in the mouth in less than 10 seconds and completely dissolved within less than 50 seconds.
  • composition gelatine capsule amounts in% by weight ingredient
  • a Gelatin shell glycerin 2,014 Gelatin 240 Bloom 7.91 sucralose 0,065 Allura red 0,006 brilliant Blue 0.005
  • Core composition Vegetable oil triglyceride (coconut oil fraction) 79.49 Orange flavor containing 1% by weight of homoeriodictyol based on the total weight of the flavor 10.0 Rebaudioside A 98% 0.05 2-Hydroxypropylmenthylcarbonat 0.33 vanillin 0.07
  • Parts A to D are mixed and kneaded intensively.
  • the raw material can be processed into ready-to-eat chewing gum in the form of thin strips, for example.
  • Table 6 ⁇ / b> Composition of chewing gum - amounts in% by weight part preparation A
  • tea and semi-finished goods are mixed and packaged in teabags made of filter paper.
  • a tea bag is poured into 100 - 250 ml of boiling water and left for 2 - 5 min.
  • Table 8 ⁇ / b> Tea beverage composition - amounts in% by weight preparation A green tea, China, leaf products 91,90 Semifinished product B from application example 2 8.0 Aroma (type lemon) 0.1
  • a bitter chocolate was made from the following raw materials and then poured into rectangular molds.
  • Table 9 ⁇ / b> Composition of chocolate - amounts in% by weight preparation A cocoa paste 55.55 cocoa butter 11,70 sugar 29,50 skimmed milk 3.00 lecithin 0.2 vanillin 0,035 Homoeriodictyol 10% in ethanol 0.05
  • Palatinit was mixed with water and the mixture was melted at 165 ° C and then cooled to 115 ° C. The remaining ingredients were added and poured into molds after mixing, removed from the molds after solidification and then individually packaged.
  • Table 10 ⁇ / b> Caramel composition - by weight as% by weight preparation A B C Palatinit, type M.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Nutrition Science (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Toxicology (AREA)
  • Mycology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Description

GEBIET DER ERFINDUNGFIELD OF THE INVENTION

Die Erfindung befindet sich auf dem Gebiet der Pharmazie und Nahrungsmittel und betrifft Zubereitungen, die Wirkstoffe gegen die durch Nahrungsmittelbestandteile induzierte Sekretion von Magensäure enthalten.The invention is in the field of pharmacy and foodstuffs and relates to preparations containing active ingredients against food constituent-induced secretion of gastric acid.

STAND DER TECHNIKSTATE OF THE ART

Die Stimulation der Magensäuresekretion stellt einen wichtigen Mechanismus zur Einleitung der Verdauung von Nahrung, insbesondere proteinreicher Nahrung dar. Es kann durchaus positiv für die Verdauung sein, die Sekretion kurzfristig maßvoll zusätzlich anzuregen. Wird Magensäure aber durch externe Stimuli übermäßig sekretiert und somit der pH im Magen zu stark gesenkt, so führt das akut in der Regel z.B. zu Unwohlsein oder saurem Aufstoßen. Wenn dieser Zustand länger anhält oder chronisch die Magensäuresekretion stark angeregt wird, so können entzündliche Zustände der Magenschleimhaut sowie der Speiseröhre induziert werden, die ihrerseits wiederum als Spätfolge Geschwüre und im schlimmsten Fall auch bösartige Gewebeveränderungen bis zum Magenkrebs und Speiseröhrenkrebs auslösen.The stimulation of gastric acid secretion is an important mechanism for the initiation of digestion of food, especially protein-rich food dar. It may be quite positive for the digestion, the moderate additional short-term stimulation in addition. However, if gastric acid is excessively secreted by external stimuli and thus the pH in the stomach is lowered too much, this usually results, for example, acutely. to malaise or acid regurgitation. If this condition lasts longer or chronic gastric acid secretion is greatly stimulated, it can induce inflammatory conditions of the gastric mucosa and the esophagus, in turn, as ulceration late ulcer and in the worst case, even malignant tissue changes to gastric cancer and esophageal cancer.

Die Magensäuresekretion wird neben den allgemeinen Stimuli wie Nahrungsaufnahme, Hungerzustände etc. auch durch diverse niedermolekulare Nahrungsbestandteile induziert. Z.B. wird von Liszt et al. in J. AGRIC FOOD CHEM. 60, 7022-7030 (2012 ) beschrieben, dass die in Weißwein verstärkt vorkommenden Fruchtsäuren Äpfelsäure und Bernsteinsäure einen wesentlichen Beitrag zur übermäßigen Säuresekretion liefern, die im Falle der Weinsäure aber durch Alkohol wieder gemildert werden kann. Auch können Hopfeninhaltsstoffe z.B. über Bierkonsum zu einer Ausschüttung von Protonen in den Mageninhalt induzieren (vgl. Walker et al. in J. AGRIC FOOD CHEM. 60, 1405-1412 (2012 ), wobei eine Tendenz der relativen Bitterkeit und der Aktivität auf die Protonensekretion zu erkennen ist. Auch Kaffee und insbesondere das darin enthaltende Coffein ist in der Lage, Magensäuresekretion signifikant zu stimulieren, wie von Rubach et al., in MOL. NUTR. FOOD RES. 56, 325-335 (2012 ) gezeigt werden konnte.Gastric acid secretion is induced in addition to the general stimuli such as food intake, starvation, etc., also by various low-molecular food components. For example, will from Liszt et al. in J. AGRIC FOOD CHEM. 60, 7022-7030 (2012 ) , that the fruit acids, malic acid and succinic acid, which are increasingly found in white wine, make a significant contribution to excessive acid secretion, which in the case of tartaric acid can be alleviated by alcohol. Also, hop ingredients can induce eg via beer consumption to a release of protons in the stomach contents (see. Walker et al. in J. AGRIC FOOD CHEM. 60, 1405-1412 (2012 ), showing a tendency of relative bitterness and activity on proton secretion. Also, coffee, and especially the caffeine contained therein, is able to significantly stimulate gastric acid secretion, such as Rubach et al., In MOL. NUTR. FOOD RES. 56, 325-335 (2012 ) could be shown.

Aus dem Aufsatz von Monforte et al. mit dem Titel "Protective effect of Calamintha officinalis Moench leaves against alcohol-induced gastric mucosa injury in rats" in PHY-TOTHERAPY RES 26(6), S. 839-844 (2012 ) ist bekannt, dass der Mechanismus der Ulkusbildung bei Ethanolgabe unter anderem in der Induktion der Protonensekretion gesehen wird. Die gastroprotektive Wirkung des Extraktes wird dabei auf die verschiedenen Bestandteile, insbesondere auf die Anwesenheit von Eriodyctyol zurückgeführt, wobei eine inhibitorische Wirkung dieser Stoffe auf die H+K+ ATPase unterstellt wird.From the essay of Monforte et al. entitled "Protective effect of Calamintha officinalis Moench leaves against alcohol-induced gastric mucosa injury in rats" in PHY-TOTHERAPY RES 26 (6), pp. 839-844 (2012 ) it is known that the mechanism of ulcer formation in ethanol administration is seen, inter alia, in the induction of proton secretion. The gastroprotective effect of the extract is attributed to the various constituents, in particular to the presence of eryodyctyol, whereby an inhibitory effect of these substances on the H + K + ATPase is assumed.

Klassisch verwendet man zwei große Gruppen von Wirkstoffen zur Reduktion der oben beschriebenen Magensäuresekretion: Neutralisation der Magensäure mit Hilfe von basischen Materialien wie Natriumhydrogencarbonat, Calciumcarbonat, basischen Aluminium- oder Magnesiumhydroxiden etc. auf der einen Seite zu Anhebung des pH-Wertes; andererseits Senkung der Magensäuresekretion durch direkte Blockierung der auf den sekretorischen Zellen (Parietalzellen) zu findenden Acetylcholin-Rezeptoren (M3-Typ) durch Wirkstoffe wie Pirenzepin oder öfter H2-Histaminrezeptoren z.B. durch Wirkstoffe wie Cimetidin, Ranitidin oder Famotidin; als drittes Wirkprinzip wird direkt die ATP-getriebene Protonenpumpe der Parietalzellen moduliert (Opremazol).Classically, two major groups of drugs are used to reduce gastric acid secretion as described above: neutralization of gastric acid with the aid of basic materials such as sodium bicarbonate, calcium carbonate, basic aluminum or magnesium hydroxides etc. on the one hand to increase the pH; on the other hand, reduction of gastric acid secretion by direct blocking of the acetylcholine receptors (M 3 type) on the secretory cells (parietal cells) by active substances such as pirenzepine or more frequently H 2 histamine receptors, for example by active substances such as cimetidine, ranitidine or famotidine; as a third principle, the ATP-driven proton pump of the parietal cells is directly modulated (Opremazol).

Der Mechanismus der stimulierenden Wirksamkeit der oben genannten Nahrungsmittelbestandteile ist in der Regel nicht klar. Daher ist auch nicht vorhersehbar, welche für oder in Nahrungsmittel verwendbare niedermolekulare Stoffe (außer basischen Stoffen durch ihre Pufferwirkung) gegebenenfalls auch die Wirkung umkehren können und somit die übermäßige Sekretion verringern können.The mechanism of stimulating activity of the above-mentioned food ingredients is usually not clear. Therefore, it is also unpredictable which low-molecular substances which can be used for or in foods (as well as basic substances due to their buffering action) may possibly also reverse the action and thus reduce excessive secretion.

Aufgabe der Erfindung war es daher, für oder in Nahrungsmittel verwendbare niedermolekulare Stoffe, bevorzugt natürliche Stoffe zu finden, die sich gegenüber den bekannten Wirkstoffen durch eine bessere Verträglichkeit und höhere Leistungsfähigkeit auszeichnen und die durch die oben genannten Nahrungsmittelbestandteile induzierte Säuresekretion mindern oder sogar vollständig verhindern können.The object of the invention was therefore to find usable for or in food low molecular weight substances, preferably natural substances that are distinguished from the known active ingredients by better tolerability and higher performance and reduce the induced by the above food ingredients acid secretion or even completely prevent ,

BESCHREIBUNG DER ERFINDUNGDESCRIPTION OF THE INVENTION

Ein erster Gegenstand der Erfindung betrifft pharmazeutische Zubereitungen, enthaltend
bitter-maskierend wirkende Hydroxyflavanonen ausgewählt aus der Gruppe bestehend aus Eriodictyol-7-methylether, Homoeriodictyol, und deren Natrium-, Kalium-, Calcium-, Magnesium- oder Zinksalzen (Komponente a)
zur Verwendung zur Verminderung und/oder Inhibierung der von Nahrungsmittelbestandteilen (Komponente b) induzierten Magensäuresekretion,
ausgewählt aus der Gruppe, die gebildet wird von Xanthin, Fruchtsäuren, phenolischen Glykosiden, Flavonglykosiden, Dihydrochalconglykosiden, hydrolysierbaren und nicht-hydrolysierbaren Tanninen und deren Oligomeren, terpenoiden oder iridoiden Bitterstoffen und Triterpenglykosiden sowie deren Gemischen.A first subject of the invention relates to pharmaceutical preparations containing
bitter-masking hydroxyflavanones selected from the group consisting of eriodictyol-7-methyl ether, homoeriodictyol, and their sodium, potassium, calcium, magnesium or zinc salts (component a)
for use in reducing and / or inhibiting gastric acid secretion induced by food ingredients (component b),
selected from the group formed by xanthine, fruit acids, phenolic glycosides, flavone glycosides, dihydrochalcone glycosides, hydrolyzable and nonhydrolyzable tannins and their oligomers, terpenoid or iridoid bitter substances and triterpene glycosides and mixtures thereof.

Überraschenderweise wurde gefunden, dass Stoffe, die in der Lage sind die Bitterkeit vieler Nahrungsmittel zu maskieren, auch gleichzeitig die durch diese Stoffe induzierte Sekretion von Magensäure vermindern oder sogar inhibieren. Insbesondere wurde festgestellt, dass die Stoffe der Gruppe (a), wie z.B. Homoeriodictyol, Eriodictyol, Matairesinol, Lariciresinol oder Enterolacton die magensäurestimulierende Wirkung der Stoffe der Gruppe (b), wie z.B. Coffein oder Theobromin, in Kombination wieder senken oder gänzlich blockieren können.Surprisingly, it has been found that substances which are able to mask the bitterness of many foods also simultaneously reduce or even inhibit the gastric acid secretion induced by these substances. In particular, it has been found that the substances of group (a), e.g. Homoeriodictyol, eriodictyol, matairesinol, lariciresinol or enterolactone the gastric acid stimulating effect of the substances of group (b), such. Caffeine or theobromine, in combination lower again or block completely.

Dies ist umso erstaunlicher, als man bislang davon ausgegangen ist, dass die Maskierungsstoffe lediglich an bestimmte Geschmacksrezeptoren andocken und nicht auch noch eine pharmakologische Wirkung besitzen. Die Verwendung der Maskierungsstoffe für den angegebenen Zweck hat dabei den weiteren Vorteil, dass sie sich bereits als ausgesprochen bekömmlich erwiesen haben.This is all the more surprising, as it has been assumed that the masking agents dock only to certain taste receptors and not also have a pharmacological effect. The use of the masking agents for the stated purpose has the further advantage that they have already proven to be extremely digestible.

BITTER-MASKIERENDE STOFFE Die bitter-maskierende Stoffe, die die Komponente (a) bilden, stellen wie erwähnt Hydroxyflavanone dar, insbesondere Eriodictyol, Eriodictyol-7-methylether, Homoeriodictyol, und deren Natrium-, Kalium-, Calcium-, Magnesium- oder Zinksalzen, speziell solches wie sie in der Europäischen Patentanmeldung EP 1258200 A2 beschrieben werden. BITTER MASKING SUBSTANCES The bitter-masking agents constituting component (a) are, as mentioned, hydroxyflavanones, especially eriodictyol, eriodictyol-7-methyl ether, homoeriodictyol, and their salts of sodium, potassium, calcium, magnesium or zinc , especially such as those in the European patent application EP 1258200 A2 to be discribed.

SEKRETION VON MAGENSÄURE INDUZIERENDE NAHRUNGSMITTELBESTANDTEILESECRETION OF MAGIC ACID INDUCING FOOD STUFFS

Diese Stoffe, die die Komponente (b) umfassen, sind ausgewählt aus der Gruppe, die gebildet wird von:

  • Xanthine, insbesondere Coffein, Theobromin und Theophyllin;
  • Fruchtsäuren, insbesondere Weinsäure, Traubensäure, Äpfelsäure und Bernsteinsäure;
  • phenolische Glycoside, insbesondere Salicin und Arbutin;
  • Flavanonglycoside, insbesondere Neohesperedin, Eriocitrin, Neoeriocitrin, Narirutin und Naringin;
  • Dihydrochalconglycoside, insbesondere Phloridzin, Trilobatin;
  • hydrolisierbare Tannine, insbesondere Gallus- oder Ellagsäureester von Kohlenhydraten, z.B. Pentagalloylglucose;
  • nicht-hydrolisierbare Tannine, insbesondere galloylierte Catechine oder Epicatechine und deren Oligomeren, z.B. Proanthyocyanidine oder Procyanidine, Thearubigenin), Flavone und deren Glycoside, insbesondere Quercetin, Quercitrin, Rutin, Taxifolin, Myricetin, Myrictrin;
  • terpenoide Bitterstoffe, insbesondere Limonin, Nomilin, Lupolone und Humolone;
  • Triterpenglycoside, insbesondere Stevioside, Rubusosid, Steviosid, Rebaudiosid A, Rebaudioside C, Glycyrrhizin (Glycyrrhizinsäure) und Glycyrrhetinsäure); und
  • iridoide Bitterstoffe wie z.B. Oleuropein
sowie deren Gemische.These substances comprising component (b) are selected from the group formed by:
  • Xanthines, especially caffeine, theobromine and theophylline;
  • Fruit acids, in particular tartaric acid, grape acid, malic acid and succinic acid;
  • phenolic glycosides, especially salicin and arbutin;
  • Flavanone glycosides , in particular neohesperedin, eriocitrin, neoeriocitrin, narirutin and naringin;
  • Dihydrochalconglycosides, especially phloridzin, trilobatin;
  • hydrolyzable tannins, in particular gallic or ellagic acid esters of carbohydrates, for example pentagalloylglucose;
  • nonhydrolyzable tannins, in particular galloylated catechins or epicatechins and their oligomers, for example proanthocyanidins or procyanidins, thearubigenin), flavones and their glycosides, in particular quercetin, quercitrin, rutin, taxifolin, myricetin, myrictrin;
  • terpenoid bittering agents , especially limonin, nomilin, lupolone and humolone;
  • Triterpene glycosides, especially steviosides, rubusoside, stevioside, rebaudioside A, rebaudioside C, glycyrrhizin (glycyrrhizic acid), and glycyrrhetinic acid); and
  • iridoid bitter substances such as oleuropein
as well as their mixtures.

BEVORZUGTE AUSFÜHRUNGSFORMENPREFERRED EMBODIMENTS

Die stärkste Verminderung bzw. eine vollständige Inhibierung der induzierten Magensäuresekretion wurde in Zubereitungen beobachtet, die als Komponente (b) Coffein und/oder Theobromin enthielten und denen man vorzugsweise Homoeriodictyol

Figure imgb0001
zusetzt.The greatest reduction or complete inhibition of the induced gastric acid secretion was observed in preparations containing caffeine and / or theobromine as component (b) and preferably homoeriodictyol
Figure imgb0001
 added.

Grundsätzlich können die therapeutischen Zubereitungen sowohl die Stoffe, die die Komponente (a) als auch (b) bilden, jeweils in Mengen von etwa 0,1 mg/kg (entsprechend 0,1 ppm) bis etwa 1 Gew.-% enthalten. Vorzugsweise sind die Stoffe jedoch jeweils in Mengen von etwa 0,5 bis etwa 1.000 mg/kg (entsprechend etwa 0,5 bis etwa 1.000 ppm), bevorzugt von etwa 1 bis etwa 500 mg/kg, weiter bevorzugt von etwa 3 bis etwa 300 mg/kg, besonders bevorzugt von etwa 5 bis etwa 200 mg/kg und am meisten bevorzugt von etwa 10 bis 100 mg/kg enthalten.In principle, the therapeutic preparations may contain both the components constituting components (a) and (b) in amounts of from about 0.1 mg / kg (corresponding to 0.1 ppm) to about 1% by weight. Preferably, however, the materials are each in amounts of from about 0.5 to about 1000 mg / kg (corresponding to about 0.5 to about 1000 ppm), preferably from about 1 to about 500 mg / kg, more preferably from about 3 to about 300 mg / kg, more preferably from about 5 to about 200 mg / kg, and most preferably from about 10 to 100 mg / kg.

Die erfindungsgemäßen Zubereitungen können die Stoffe, die die Komponenten (a) und (b) bilden, im Gewichtsverhältnis von etwa 1:100 bis etwa 1:1, vorzugsweise 1:90 bis etwa 1:2 und insbesondere von etwa 1:5 bis etwa 1:10 enthalten.The compositions of the invention may comprise the materials which form components (a) and (b) in a weight ratio of from about 1: 100 to about 1: 1, preferably 1:90 to about 1: 2, and more preferably from about 1: 5 to about 1:10 included.

ORALE ZUBEREITUNGENORAL PREPARATIONS

Ein weiterer Gegenstand der vorliegenden Erfindung betrifft speziell der Ernährung oder dem Genuss dienende Zubereitungen zur oralen Aufnahme, enthaltend wie vorstehend bereits ausführlich erläutert

  1. (a) bitter-maskierend wirkende Hydroxyflavanone ausgewählt aus der Gruppe bestehend aus Eriodictyol-7-methylether, Homoeriodictyol, und deren Natrium-, Kalium-, Calcium-, Magnesium- oder Zinksalzen (Komponente a), und
  2. (b) Stoffe die die Sekretion von Magensäure induzieren, ausgewählt aus der Gruppe, die gebildet wird von Xanthin, Fruchtsäuren, phenolischen Glykosiden, Flavonglykosiden, Dihydrochalconglykosiden, hydrolysierbaren und nicht-hydrolysierbaren Tanninen und deren Oligomeren, terpenoiden oder iridoiden Bitterstoffen und Triterpenglykosiden sowie deren Gemischen (Komponente b),
A further subject matter of the present invention relates to preparations for oral intake which are especially useful for nutrition or enjoyment, as already explained in detail above
  1. (a) bitter-masking hydroxyflavanones selected from the group consisting of eriodictyol-7-methyl ether, homoeriodictyol, and their sodium, potassium, calcium, magnesium or zinc salts (component a), and
  2. (b) substances inducing the secretion of gastric acid selected from the group consisting of xanthine, fruit acids, phenolic glycosides, flavone glycosides, dihydrochalcone glycosides, hydrolyzable and non-hydrolyzable tannins and their oligomers, terpenoid or iridoid bitter and triterpene glycosides, and mixtures thereof (Component b),

wobei sich die Zubereitungen dadurch auszeichnen, dass sie die Komponente (a) und (b) jeweils in Mengen von 3 bis 300 ppm enthalten.wherein the preparations are characterized in that they contain the component (a) and (b) respectively in amounts of 3 to 300 ppm.

Der Ernährung oder dem Genuss dienende (d.h. zum Verzehr geeignete) Zubereitungen sind im Rahmen dieser Erfindung z.B. Backwaren (z.B. Brot, Trockenkekse, Kuchen, sonstiges Gebäck), Süßwaren (z.B. Schokoladen, Schokoladenriegelprodukte, sonstige Riegelprodukte, Fruchtgummi, Hart- und Weichkaramellen, Kaugummi), alkoholische oder nicht-alkoholische Getränke (z.B. Kaffee, Tee, Wein, weinhaltige Getränke, Bier, bierhaltige Getränke, Liköre, Schnäpse, Weinbrände, fruchthaltige Limonaden, isotonische Getränke, Erfrischungsgetränke, Nektare, Obst- und Gemüsesäfte, Frucht- oder Gemüsesaftzubereitungen), Instantgetränke (z.B. Instant-Kakao-Getränke, Instant-Tee-Getränke, Instant-Kaffeegetränke), Fleischprodukte (z.B. Schinken, Frischwurst- oder Rohwurstzubereitungen, gewürzte oder marinierte Frisch- oder Pökelfleischprodukte), Eier oder Eiprodukte (Trockenei, Eiweiß, Eigelb), Getreideprodukte (z.B. Frühstückscerealien, Müsliriegel, vorgegarte Fertigreis-Produkte), Milchprodukte (z.B. Milchgetränke, Milcheis, Joghurt, Kefir, Frischkäse, Weichkäse, Hartkäse, Trockenmilchpulver, Molke, Butter, Buttermilch, teilweise oder vollständig hydrolisierte Milchprotein-haltige Produkte), Produkte aus Sojaprotein oder anderen Sojabohnen-Fraktionen (z.B. Sojamilch und daraus gefertigte Produkte, Sojalecithin-haltige Zubereitungen, fermentierte Produkte wie Tofu oder Tempe oder daraus gefertigte Produkte, Sojasoßen), Fruchtzubereitungen (z.B. Konfitüren, Fruchteis, Fruchtsoßen, Fruchtfüllungen), Gemüsezubereitungen (z.B. Ketchup, Soßen, Trockengemüse, Tiefkühlgemüse, vorgegarte Gemüse, in Essig eingelegte Gemüse, eingekochte Gemüse), Knabberartikel (z.B. gebackene oder frittierte Kartoffelchips oder Kartoffelteigprodukte, Brotteigprodukte, Extrudate auf Mais- oder Erdnussbasis), Produkte auf Fett- und Ölbasis oder Emulsionen derselben (z.B. Mayon-naise, Remoulade, Dressings, Würzzubereitungen), sonstige Fertiggerichte und Suppen (z.B. Trockensuppen, Instant-Suppen, vorgegarte Suppen), Gewürze, Würzmischungen sowie insbesondere Aufstreuwürzungen (englisch: Seasonings), die beispielsweise im Snackbereich Anwendung finden.Nutrition or pleasure (i.e., for human consumption) preparations are within the scope of this invention, e.g. Bakery products (eg bread, dry biscuits, cakes, other pastries), confectionery (eg chocolates, chocolate bar products, other bar products, fruit gums, hard and soft caramels, chewing gum), alcoholic or non-alcoholic drinks (eg coffee, tea, wine, wine-based drinks, Beer, beer-based drinks, liqueurs, schnapps, brandies, fruit-based sodas, isotonic drinks, soft drinks, nectars, fruit and vegetable juices, fruit or vegetable juice preparations), instant drinks (eg instant cocoa drinks, instant tea drinks, instant coffee drinks ), Meat products (eg ham, fresh sausage or raw sausage preparations, spiced or marinated fresh or salted meat products), eggs or egg products (dry egg, egg whites, egg yolk), cereal products (eg breakfast cereals, muesli bars, pre-cooked finished rice products), dairy products (eg milk drinks, Milk ice cream, yoghurt, kefir, cream cheese, soft cheese, hard cheese, dried milk powder, whey, Butter, buttermilk, partially or fully hydrolyzed milk protein-containing products), soy protein or other soybean fractions (e.g. Soymilk and products made therefrom, soy lecithin-containing preparations, fermented products such as tofu or Tempe or products made therefrom, soy sauces), fruit preparations (eg jams, fruit ice cream, fruit sauces, fruit fillings), vegetable preparations (eg ketchup, sauces, dried vegetables, frozen vegetables, pre-cooked vegetables , pickled vegetables, cooked vegetables), snack foods (eg baked or fried potato chips or potato dough products, bread dough products, corn or peanut based extrudates), fat and oil based products or emulsions thereof (eg mayonnaise, remoulade, dressings, spice preparations ), other prepared meals and soups (eg dry soups, instant soups, pre-cooked soups), spices, spice mixtures and in particular seasoning spices (English: Seasonings), which are used for example in the snack area.

Die oralen Zubereitungen im Sinne der Erfindung können auch als Halbfertigware zur Herstellung weiterer oral konsumierbarer Zubereitungen dienen. Die Zubereitungen im Sinne der Erfindung können auch in Form von Kapseln, Tabletten (oral und/oder magenauflösende Tabletten), Dragees, Granulaten, Pellets, Feststoffmischungen, Dispersionen in flüssigen Phasen, als Emulsionen, als Pulver, als Lösungen, als Pasten oder als andere schluck- oder kaubare Zubereitungen als Nahrungsergänzungsmittel vorliegen.The oral preparations according to the invention can also serve as semi-finished goods for the production of other orally consumable preparations. The preparations according to the invention may also be in the form of capsules, tablets (oral and / or stomach-dissolving tablets), dragees, granules, pellets, solid mixtures, dispersions in liquid Phases, as emulsions, as powders, as solutions, as pastes or as other swallowable or chewable preparations as dietary supplements.

Bevorzugt werden dabei einer oder mehrerer der Stoffe der Gruppe (a) in eine oral konsumierbare Zubereitung, insbesondere in Form von schluckbaren Zubereitungen (z.B. Getränke, Dispersionen, Emulsionen, Pasten, im Mund oder Magen auflösbare Kapseln, Tabletten, Komprimate, Weichkaramelle, Dragees, Granulaten, Pellets, Fruchtgummis) oder ausreichende Konzentrationen Stoffe der Gruppe (a) freisetzende nicht zum Schlucken intendierte Zubereitungen (z.B. Kaugummi, Hartkaramelle) in einer wirksamen Konzentration eingearbeitet.Preference is given here one or more of the substances of group (a) in an orally consumable preparation, in particular in the form of swallowable preparations (eg drinks, dispersions, emulsions, pastes, in the mouth or stomach dissolvable capsules, tablets, compressed, soft caramel, dragees, Granules, pellets, fruit gums) or sufficient concentrations of substances of group (a) releasing non-swallowing preparations (eg chewing gum, hard caramels) incorporated in an effective concentration.

Die erfindungsgemäß einzusetzenden Stoffe der Gruppe (a) weisen in erfindungsgemäßen zum Verzehr geeignete Zubereitungen, insbesondere in den erfindungsgemäß bevorzugt einzusetzenden Konzentrationen, keinen nennenswerten Eigengeschmack auf, insbesondere zeigen sie in den (bevorzugten bzw. besonders bevorzugten) Einsatzkonzentrationen keine unangenehmen oder störenden Geschmacksnoten. Dabei sind die Stoffe der Gruppe (a) jeweils alleine und/oder in Mischung in der Lage, die Bitterkeit eines oder mehrerer der Stoffe der Gruppe (b) zu reduzieren oder ganz zu blockieren.The substances of group (a) to be used according to the invention have no significant intrinsic taste in preparations according to the invention which are suitable for consumption, in particular they show no unpleasant or disturbing taste notes in the (preferred or particularly preferred) use concentrations. The substances of group (a) alone and / or in mixture are able to reduce or completely block the bitterness of one or more of the substances of group (b).

Der oder die Stoffe der Gruppe (a) sowie erfindungsgemäßer Zubereitungen, enthaltend den oder die Stoffe der Gruppe (a), können zeitlich vor, während oder nach der oralen Einnahme von dem oder den Stoffen der Gruppe (b) oder Zubereitungen, enthaltend den oder die Stoffe der Gruppe (b) oral zugeführt werden.The substance or substances of group (a) and preparations according to the invention containing the substance (s) of group (a) may be treated before, during or after oral intake of the substance (s) of group (b) or preparations containing the or the substances of group (b) are administered orally.

Besonders vorteilhaft ist dabei die bekannte Tatsache, dass die Stoffe der Gruppe (a) regelmäßig in der Lage sind, den bitteren (unangenehmen) Geschmack der Stoffe der Gruppe (b) teilweise oder ganz zu reduzieren und somit die Akzeptanz für die Zubereitungen deutlich steigern können. Dies ist insbesondere der Fall, wenn die Stoffe der Gruppe (b) zeitlich gleichzeitig mit Stoffen der Gruppe (a) appliziert werden.Particularly advantageous is the known fact that the substances of group (a) are regularly able to partially or completely reduce the bitter (unpleasant) taste of the substances of group (b) and thus significantly increase the acceptance of the preparations , This is especially the case if the substances of group (b) are applied simultaneously with substances of group (a).

Bei nachfolgender oraler Einnahme des oder der Stoffe der Gruppe (a) sind Zubereitungsformen bevorzugt, die den oder die Stoffe der Gruppe (a) in einer Form enthalten, die eine verzögerte Freisetzung bewirken.In the case of subsequent oral intake of the substance or substances of group (a), preparation forms which contain the substance or substances of group (a) in a form which cause a delayed release are preferred.

Alternativ zur gleichzeitigen oralen Einnahme können sind auch Zubereitungen geeignet, die
einen oder mehrere der unangenehm schmeckende und magensäurestimulierende Stoffe der Gruppe (b) in einer in Bezug auf die Magensäurestimulation wirksamen Menge aufweisen und gleichzeitig einen oder mehrere der Stoffe der Gruppe (a) in einer in Bezug auf die Magensäurestimulation wirksamen Menge enthalten.As an alternative to simultaneous oral ingestion, preparations may also be suitable which
having one or more of the unpleasant tasting and gastric acid stimulants of group (b) in an amount effective in gastric acid stimulation and simultaneously containing one or more of the substances of group (a) in an amount effective in gastric acid stimulation.

Grundsätzlich können die oralen Zubereitungen - seien es Fertig- oder Halbfertigprodukte - sowohl die Stoffe, die die Komponente (a) als auch (b) bilden, jeweils in Mengen von etwa 0,1 mg/kg (entsprechend 0,1 ppm) bis etwa 1 Gew.-% enthalten. Vorzugsweise sind die Stoffe jedoch jeweils in Mengen von etwa 0,5 bis etwa 1000 mg/kg (entsprechend etwa 0,5 bis etwa 1000 ppm), bevorzugt von etwa 1 bis etwa 500 mg/kg, weiter bevorzugt von etwa 3 bis etwa 300 mg/kg, besonders bevorzugt von etwa 5 bis etwa 200 mg/kg und am meisten bevorzugt von etwa 10 bis 100 mg/kg enthalten.In principle, the oral preparations - be it finished or semi-finished products - both the substances that form the components (a) and (b), in amounts of about 0.1 mg / kg (corresponding to 0.1 ppm) to about 1 wt .-% included. Preferably, however, the substances are each in amounts of about 0.5 to about 1000 mg / kg (corresponding to about From about 1 to about 500 mg / kg, more preferably from about 3 to about 300 mg / kg, more preferably from about 5 to about 200 mg / kg, and most preferably about 10 to 100 mg / kg.

Die erfindungsgemäßen Zubereitungen können die Stoffe, die die Komponenten (a) und (b) bilden, im Gewichtsverhältnis von etwa 1:100 bis etwa 1:1, vorzugsweise 1:90 bis etwa 1:2 und insbesondere von etwa 1:5 bis etwa 1:10 enthalten.The compositions of the invention may comprise the materials which form components (a) and (b) in a weight ratio of from about 1: 100 to about 1: 1, preferably 1:90 to about 1: 2, and more preferably from about 1: 5 to about 1:10 included.

GEWERBLICHE ANWENDBARKEITINDUSTRIAL APPLICABILITY

Eine bevorzugte Methode zur Ermittlung der gewünschten Wirkung von Stoffen der Gruppe (a) zur Senkung der Wirkung der Stoffe der Gruppe (b) besteht in der Messung des intrazellulären pH-Wertes von HGT-1-Zellkulturen (human gastric tumor cell line) nach Behandlung mit den Teststoffen wie in Liszt, K. I.; Walker, J.; Somoza, V.. J. Agric Food Chem. 2012, 60, (28), 7022-7030 beschrieben. Bisher ist auf der Zelloberfläche von Magensäuresekretierenden Zellen nur der Somatostatin-Rezeptor (SSTR2) als Target für die Reduktion der Sekretion beschrieben worden; dieser Rezeptor ist auch in der HGT-1 beschrieben worden. Bisher sind diese Zellen aber immer nur in Kontakt mit potentiellen SSTR2-Regulatoren gebracht worden, die gemeinsame Verabreichung von bitteren Agonisten und potentiellen Antagonisten ist bisher nicht beschrieben worden.A preferred method for determining the desired effect of substances of group (a) to reduce the effect of substances of group (b) is to measure the intracellular pH of human gastric tumor cell line (HGT-1) cell cultures after treatment with the test substances as in Liszt, AI; Walker, J .; Somoza, V. J. Agric. Food Chem. 2012, 60, (28), 7022-7030 described. So far, on the cell surface of gastric acid-secreting cells only the somatostatin receptor (SSTR2) has been described as a target for the reduction of secretion; this receptor has also been described in the HGT-1. So far, however, these cells have always only been brought into contact with potential SSTR2 regulators, co-administration of bitter agonists and potential antagonists has not previously been described.

BEISPIELEEXAMPLES ZELLMODELLCELL MODEL

Als Zellmodell werden humane Parietalzellen, auch als human gastric tumor cell line (HGT-1) bekannt, verwendet. Diese wurden von Dr. C. Laboisse (Laboratory of Pathological Anatomy, Nantes, France ) zur Verfügung gestellt. Die Zellen werden unter den Standardbedingungen 37 °C, 5 % CO2 in DMEM (Dulbecco's Modified Eagle's Medium) mit 4 g/L Glucose, 10 % FBS, 2 % L-Glutamin und 1 % Penicillin/Streptomycin kultiviert. Für die Messung der intrazellulären Protonenkonzentration werden die Zellen mit Trypsin/EDTA behandelt, die Viabilität mittels Tryptanblaufärbung bestimmt und 100 000 Zellen/well in schwarzen 96-well Platten ausgesät.Human parietal cells, also known as human gastric tumor cell line (HGT-1), are used as the cell model. These were from Dr. C. Laboisse (Laboratory of Pathological Anatomy, Nantes, France ) made available. Cells are cultured under standard conditions 37 ° C, 5% CO 2 in DMEM (Dulbecco's Modified Eagle's Medium) with 4 g / L glucose, 10% FBS, 2% L-glutamine and 1% penicillin / streptomycin. For the measurement of the intracellular proton concentration, the cells are treated with trypsin / EDTA, the viability determined by tryptan blue staining and seeded 100,000 cells / well in black 96-well plates.

BEISPIEL 1EXAMPLE 1

Bestimmung des intrazellulären pH-Wertes von HGT-1-Zellkulturen in Gegenwart von Stoffen der Gruppe (a) und Stoffen der Gruppe (b)Determination of the intracellular pH of HGT-1 cell cultures in the presence of substances of group (a) and substances of group (b)

Zur Messung des intrazellularen pH-Wertes wird der Farbstoff 1,5 Carboxy-Seminaphto-rhodafluor Acetoxymethylester (SNARF-1-AM) verwendet. Die Zellen in den 96-well Platten werden einmal mit Krebs-Hepes-Puffer (KRHP) gewaschen und mit dem Farbstoff in der Konzentration von 3 µM gelöst in KRHP für 30 min bei 37 °C und 5 % CO2 inkubiert. Danach werden die Zellen zwei Mal mit KRHP gewaschen und mit Stoffen der Gruppe (b), beispielsweise 3 mM Coffein beziehungsweise 0,3 mM Theobromin alleine oder in Kombination mit Stoffen der Gruppe (a), beispielsweise Homoeriodictyol (HED) oder Eriodictyol oder Matairesinol, Lariciresinol bzw. Enterolacton in unterschiedlichen Konzentrationen in phenolrotfreiem DMEM im Volumen von 100 µL aufgetragen; als weiteres Kontrollexperiment werden die oben genannten Stoffe der Gruppe (a) alleine geprüft. Homoeriodictyol wird in doppelt destilliertem Wasser gelöst während Eriodictyol, Matairesinol, Lariciresinol bzw. Enterolacton in Ethanol (EtOH) gelöst werden. Die finale Konzentration an Lösungsmittel, die den Zellen zugeführt wird, beträgt maximal 1 %. Der Fluoreszenzfarbstoff wird bei der Wellenlänge von 488 nm angeregt und die Emission bei 580 nm und 640 nm gemessen. Das Verhältnis der Fluoreszenzwerte von 580 nm zu 640 nm wird aufgetragen im Vergleich zur Kalibrierkurve, woraus der pH-Wert ermittelt werden kann. Für die Kalibrierkurve werden die Zellen mit einem Kaliumpuffer unterschiedlicher pH-Werte von 7,2 - 8,2 pH und 2 µM Nigericin behandelt. Nigericin equilibriert den intrazellulären und extrazellulären pH-Wert, sodass der intrazelluläre pH-Wert definiert werden kann. Die intrazelluläre H+ - Konzentration wird aus dem intrazellulären pH-Wert ermittelt. Der intrazelluläre Protonenindex (IPX) wird kalkuliert durch log2 Transformation des Verhältnisses zwischen behandelten Zellen und unbehandelten Zellen (Kontrolle). Die hier dargestellten Ergebnisse werden als prozentuale Veränderung im Vergleich zu nicht-behandelten Kontrollzellen angegeben (vgl. Malte Rubach, R. L., Elisabeth Seebach, Mark M. Somoza, Thomas Hofmann; Somoza, a. V., Mol Nutr Food Res. in press, 2011 ; Rubach, M.; Lang, R.; Hofmann, T.; Somoza, V., Ann N Y Acad Sci 2008, 1126, 310-4 ; Rubach, M.; Lang, R.; Skupin, C.; Hofmann, T.; Somoza, V., J Agric Food Chem 2010, 58, 4153-61 ; Weiss, C.; Rubach, M.; Lang, R.; Seebach, E.; Blumberg, S.; Frank, O.; Hofmann, T.; Somoza, V., J Agric Food Chem 2010, 58, 1976-85 ; Liszt, K. I.; Walker, J.; Somoza, V., J Agric Food Chem 2012 ; Walker, J.; Hell, J.; Liszt, K. I.; Dresel, M.; Pignitter, M.; Hofmann, T.; Somoza, V., J Agric Food Chem 2012, 60, 1405-12 ). Die Anzahl der angegebenen Replikate beziehen sich auf technische Replikate (tr) oder auf die Anzahl an Gesamtreplikaten (n), die sich aus der Anzahl der technischen Replikate multipliziert mit der Anzahl an biologischen Replikaten ergibt.To measure the intracellular pH, the dye 1.5 carboxy-seminaphtho-rhodafluoro acetoxymethyl ester (SNARF-1-AM) is used. The cells in the 96-well plates are washed once with Krebs-Hepes buffer (KRHP) and incubated with the dye in the concentration of 3 μM dissolved in KRHP for 30 min at 37 ° C and 5% CO 2 . Thereafter, the cells are washed twice with KRHP and with substances of group (b), for example 3 mM caffeine or 0.3 mM theobromine alone or in combination with substances of group (a), for example homoeriodictyol (HED) or eriodictyol or matairesinol, Lariciresinol or enterolactone in different concentrations in phenolrotfreien DMEM volume of 100 μL applied; as a further control experiment, the abovementioned substances of group (a) alone are tested. Homoeriodictyol is dissolved in double-distilled water while eriodictyol, matairesinol, lariciresinol or enterolactone are dissolved in ethanol (EtOH). The final concentration of solvent supplied to the cells is at most 1%. The fluorescent dye is excited at the wavelength of 488 nm and the emission is measured at 580 nm and 640 nm. The ratio of the fluorescence values from 580 nm to 640 nm is plotted in comparison to the calibration curve, from which the pH value can be determined. For the calibration curve, the cells are treated with a potassium buffer of pH 7.2 - 8.2 pH and 2 μM Nigericin. Nigericin equilibrates the intracellular and extracellular pH so that the intracellular pH can be defined. The intracellular H + concentration is determined from the intracellular pH. The intracellular proton index (IPX) is calculated by log2 transformation of the ratio between treated cells and untreated cells (control). The results presented here are expressed as a percentage change compared to untreated control cells (cf. Malte Rubach, RL, Elisabeth Seebach, Mark M. Somoza, Thomas Hofmann; Somoza, a. V., Mol Nutr Food Res. In press, 2011 ; Rubach, M .; Lang, R .; Hofmann, T .; Somoza, V., Ann NY Acad Sci 2008, 1126, 310-4 ; Rubach, M .; Lang, R .; Skupin, C .; Hofmann, T .; Somoza, V., J Agric Food Chem 2010, 58, 4153-61 ; Weiss, C .; Rubach, M .; Lang, R .; Seebach, E .; Blumberg, S .; Frank, O .; Hofmann, T .; Somoza, V., J Agric Food Chem 2010, 58, 1976-85 ; Liszt, AI; Walker, J .; Somoza, V., J Agric Food Chem 2012 ; Walker, J .; Hell, J .; Liszt, AI; Dresel, M .; Pignitter, M .; Hofmann, T .; Somoza, V., J Agric Food Chem 2012, 60, 1405-12 ). The number of indicated replicates refers to technical replicas (tr) or to the number of total replicates (n), which is the number of technical replicates multiplied by the number of biological replicates.

In der folgenden Tabelle 1A ist die prozentuale Steigerung der Protonensekretion in HGT-1 Zellen im Vergleich zu unbehandelten Kontrollen nach 10 minütiger Stimulierung durch DMEM oder DMEM mit ETOH 1% oder 1mM Histamin oder 3 mM Coffein mit und ohne EtOH 1% angegeben. Die Daten sind dargestellt als Mittelwert und mittlere Standardabweichung, n=21-37, tr=6. Statistik: one-way Anova mit post-hoc Test nach Dunn's. Signifikante Unterschiede (p < 0,05) werden durch Buchstaben angegeben. Tabelle 1A Vergleichsbeispiel Steigerung der Sekretion durch Stoffe der Gruppe (b) Testsubstanz T/C [%] SEM Kontrolle (DMEM) 0.150 1.00 a EtOH 1% 14.44 2.61 b 1 mM Histamin 27.42 3.17 b 3 mM Coffein 48.87 3.64 d 3 mM Coffein + EtOH 1% 44.92 3.51 d In Table 1A below , the percent increase in proton secretion in HGT-1 cells is given as compared to untreated controls after 10 minutes of stimulation by DMEM or DMEM with ETOH 1% or 1 mM histamine or 3 mM caffeine with and without EtOH 1%. The data are presented as mean and mean standard deviation, n = 21-37, tr = 6. Statistics: one-way Anova with post-hoc test after Dunn's. Significant differences (p <0.05) are indicated by letters. <b> Table 1A </ b> Comparative Example Increasing the Secretion by Substances of the Group (b) test substance T / C [%] SEM Control (DMEM) 0150 1.00 a EtOH 1% 14:44 2.61 b 1 mM histamine 27.42 3.17 b 3mM caffeine 48.87 3.64 d 3mM caffeine + EtOH 1% 44.92 3.51 d

In der folgenden Tabelle 1B ist die prozentuale Steigerung der Protonensekretion in HGT-1 Zellen im Vergleich zu unbehandelten Kontrollen nach 10 minütiger Stimulierung durch DMEM oder DMEM mit ETOH 1% oder 1mM Histamin oder 0.3 mM Theobromin mit und ohne EtOH 1% angegeben. Die Daten sind dargestellt als Mittelwert und mittlere Standardabweichung, n=21-37, tr=6. Statistik: one-way Anova mit post-hoc Test nach Dunn's. Signifikante Unterschiede (p < 0,05) werden durch Buchstaben angegeben. Tabelle 1B Vergleichsbeispiel Steigerung der Sekretion durch Stoffe der Gruppe (b) Testsubstanz T/C [%] SEM DMEM (Kontrolle) 0.15 1.00 a EtOH 1% 14.44 2.61 b 1 mM Histamin 27.42 3.17 b,c 0.3 mM Theobromin 17.51 2.65 b 0.3 mM Theobromin + EtOH 1% 32.11 2.49 c,d Table 1 B shows the percentage increase in proton secretion in HGT-1 cells compared to untreated controls after 10 minutes of stimulation by DMEM or DMEM with ETOH 1% or 1 mM histamine or 0.3 mM theobromine with and without EtOH 1%. The data are presented as mean and mean standard deviation, n = 21-37, tr = 6. Statistics: one-way Anova with post-hoc test after Dunn's. Significant differences (p <0.05) are indicated by letters. <b> Table 1B </ b> Comparative Example Increasing the Secretion by Substances of the Group (b) test substance T / C [%] SEM DMEM (control) 12:15 1.00 a EtOH 1% 14:44 2.61 b 1 mM histamine 27.42 3.17 b, c 0.3 mM theobromine 17:51 2.65 b 0.3 mM theobromine + EtOH 1% 32.11 2.49c, d

In der folgenden Tabelle 2 ist die prozentuale Steigerung der Protonensekretion in HGT-1 Zellen im Vergleich zu unbehandelten Kontrollen nach 10 minütiger Stimulierung durch DMEM (Kontrolle) oder Homoeriodictyol (HED) in unterschiedlichen Konzentrationen angegeben. Die Daten sind dargestellt als Mittelwert und mittlere Standardabweichung, n=4, tr=6. Statistik: one-way Anova mit post-hoc Test nach Dunn's. Signifikante Unterschiede (p < 0,05) werden durch Buchstaben angegeben. Tabelle 2 Beeinflussung der Sekretion durch Stoffe der Gruppe (a) Testsubstanz T/C [%] SEM DMEM (Kontrolle) -1.43 2.01 a 0.003 mM HED -8.04 3.88 a 0.03 mM HED 12.70 4.02 a 0.3 mM HED -3.66 5.24 a Table 2 below shows the percentage increase in proton secretion in HGT-1 cells compared to untreated controls after 10 minutes of stimulation by DMEM (control) or homoeriodictyol (HED) at different concentrations. The data are presented as mean and mean standard deviation, n = 4, tr = 6. Statistics: one-way Anova with post-hoc test after Dunn's. Significant differences (p <0.05) are indicated by letters. <b> Table 2 </ b> Influence of secretion by substances of group (a) test substance T / C [%] SEM DMEM (control) -1.43 2.01 a 0.003 mM HED -8.04 3.88 a 0.03 mM HED 12.70 4.02 a 0.3mM HED -3.66 5.24 a

ANWENDUNGSBEISPIEL 1APPLICATION EXAMPLE 1 Sprühgetrocknete Zubereitung als Halbfertigware zur Herstellung von FertigwarenSpray-dried preparation as semi-finished product for the production of finished goods

Das Trinkwasser wird in einem Behälter vorgelegt und das Maltodextrin und das Gummi Arabicum darin gelöst. Anschließend werden die Stoffe der Gruppe (a) mit einem Turrax in die Trägerstofflösung emulgiert. Die Temperatur der Sprühlösung sollte 30°C nicht überschreiten. Das Gemisch wird dann sprühgetrocknet (Solltemperatur Eingang: 185 - 195°C, Solltemperatur Ausgang: 70 - 75°C). Die sprühgetrocknete Halbfertigware enthält ca. 18 - 22 % der Verbindungen der Gruppe (a). Tabelle 3 Zusammensetzung Halbfertigware - Mengenangaben als Gew.-% Zubereitung A B Trinkwasser 60,8 60,8 Maltodextrin aus Weizen 24,3 24,3 Gummi Arabicum 6,1 6,1 Homoeriodictyol 8,8 4,4 The drinking water is placed in a container and the maltodextrin and gum arabic dissolved therein. Subsequently, the substances of group (a) are emulsified with a Turrax in the carrier solution. The temperature of the spray solution should not exceed 30 ° C. The mixture is then spray-dried (nominal temperature input: 185-195 ° C, target temperature output: 70-75 ° C). The spray-dried semi-finished product contains about 18 - 22% of the compounds of group (a). <b> Table 3 </ b> Composition of semi-finished goods - quantities as% by weight preparation A B Drinking water 60.8 60.8 Maltodextrin from wheat 24.3 24.3 Gum arabic 6.1 6.1 homoeriodictyol 8.8 4.4

ANWENDUNGBEISPIEL 2APPLICATION EXAMPLE 2 Trinkbare EisteezubereitungDrinkable ice tea preparation

Die Verbindungen der Gruppe (a) wurden jeweils 10 % in Ethanol vorgelöst. Schwarztee-Extrakt wurde in Wasser gelöst und zusammen mit Zucker, einer Aromazubereitung (Pfirsichgeschmack), sowie den ethanolischen Lösungen der Verbindungen der Gruppe (a) in einem Becherglas verrührt. Tabelle 4 Zusammensetzung Eistee - Mengenangaben als Gew.-% Zubereitung A Schwarztee-Extrakt 1,4 Wasser 89,5 Aromazubereitung (Typ Pfirsich) 0,65 Zucker 7,0 Zitronensäure (kristallin) 1,2 Ascorbinsäure 0,2 Homoeriodictyol in Ethanol (10 %) 0,05 The compounds of group (a) were each pre-dissolved in ethanol at 10%. Black tea extract was dissolved in water and stirred together with sugar, a flavoring preparation (peach flavor), and the ethanolic solutions of the compounds of group (a) in a beaker. <b> Table 4 </ b> Composition of iced tea - quantities by weight preparation A Black tea extract 1.4 water 89.5 Aroma preparation (type peach) 0.65 sugar 7.0 Citric acid (crystalline) 1.2 ascorbic acid 0.2 Homoeriodictyol in ethanol (10%) 0.05

ANWENDUNGSBEISPIEL 3APPLICATION EXAMPLE 3 Gelatinekapseln ohne Stoffe der Gruppe (b) zum Direktverzehr nach Applikation von Stoffen der Gruppe (b)Gelatin capsules without substances of group (b) for direct consumption after application of substances of group (b)

Die zum Direktverzehr geeigneten Gelatinekapseln wurden gemäß WO 2004/050069 hergestellt und hatten einen Durchmesser von 5 mm, das Gewichtsverhältnis von Kernmaterial zu Hüllmaterial lag bei 90:10. Die Kapseln öffneten sich im Mund innerhalb von weniger als 10 Sekunden und lösten sich vollständig innerhalb von weniger als 50 Sekunden auf. ] Tabelle 5 Zusammensetzung Gelatinekapsel - Mengenangaben als Gew.-% Inhaltsstoff A Gelatinehülle: Glycerin 2,014 Gelatine 240 Bloom 7,91 Sucralose 0,065 Allura Rot 0,006 Brillantblau 0,005 Kernzusammensetzung: Pflanzenöl-Triglycerid (Kokosöl - Fraktion) 79,49 Orangen-Aroma, enthaltend 1 Gew.-% Homoeriodictyol bezogen auf das Gesamtgewicht des Aromas 10,0 Rebaudiosid A 98 % 0,05 2-Hydroxypropylmenthylcarbonat 0,33 Vanillin 0,07 The ready-to-consume gelatin capsules were prepared according to WO 2004/050069 and had a diameter of 5 mm, the weight ratio of core material to shell material was 90:10. The capsules opened in the mouth in less than 10 seconds and completely dissolved within less than 50 seconds. ] <b> Table 5 </ b> Composition gelatine capsule - amounts in% by weight ingredient A Gelatin shell: glycerin 2,014 Gelatin 240 Bloom 7.91 sucralose 0,065 Allura red 0,006 brilliant Blue 0.005 Core composition: Vegetable oil triglyceride (coconut oil fraction) 79.49 Orange flavor containing 1% by weight of homoeriodictyol based on the total weight of the flavor 10.0 Rebaudioside A 98% 0.05 2-Hydroxypropylmenthylcarbonat 0.33 vanillin 0.07

ANWENDUNGSBEISPIEL 4APPLICATION EXAMPLE 4 Kaugummi ohne Stoff der Gruppe (b)Chewing gum without substance of the group (b)

Teile A bis D werden gemischt und intensiv geknetet. Die Rohmasse kann z.B. in Form von dünnen Streifen zu verzehrfertigen Kaugummis verarbeitet werden. ] Tabelle 6 Zusammensetzung Kaugummi - Mengenangaben als Gew.-% Teil Zubereitung A A Kaugummibase, Company "Jagum T" 30,00 B Sorbit, pulverisiert 39,00 Isomalt® (Palatinit GmbH) 9,50 Xylit 2,00 Mannit® 3,00 Aspartam® 0,10 Acesulfam® K 0,10 Emulgum® (Colloides Naturels, Inc.) 0,30 C Sorbitol, 70% 14,00 Glycerin 1,00 Tutti-Frutti-Aroma, enthaltend 1% Homoeriodictyol, bezogen auf das Gesamtgewicht des Aromas 2,00 Parts A to D are mixed and kneaded intensively. The raw material can be processed into ready-to-eat chewing gum in the form of thin strips, for example. ] <b> Table 6 </ b> Composition of chewing gum - amounts in% by weight part preparation A A Chewing gum base, Company "Jagum T" 30.00 B Sorbitol, powdered 39,00 Isomalt® (Palatinit GmbH) 9.50 xylitol 2.00 Mannit® 3.00 Aspartam® 0.10 Acesulfame® K 0.10 Emulgum® (Colloids Naturels, Inc.) 0.30 C Sorbitol, 70% 14.00 glycerin 1.00 Tutti-Frutti flavor containing 1% homoeriodictyol based on the total weight of the flavor 2.00

ANWENDUNGSBEISPIEL 5APPLICATION EXAMPLE 5 Verwendung in einem löslichen Cappuccino-GetränkUse in a soluble cappuccino drink

Die angegebenen Rohstoffe werden vermischt. Jeweils 12,5 g des hergestellten Instant-Cappuccino-Pulvers werden in 150 ml heißem Wasser gelöst. Tabelle 7 Zusammensetzung Cappuccino-Getränk - Mengenangaben als Gew.-% Zubereitung A Kaffee-Extrakt, sprühgetrocknet 16,0 Zucker 25,3 Fettpulver 18,2 Kaffeeweißer, schäumend 28,0 Hydrokolloide/ Emulgatoren 1,8 Lactose 4,7 Halbfertigware B aus Anwendungsbeispiel 1 6,0 The specified raw materials are mixed. In each case 12.5 g of the instant cappuccino powder produced are dissolved in 150 ml of hot water. <b> Table 7 </ b> Composition cappuccino beverage - amount by weight% preparation A Coffee extract, spray dried 16.0 sugar 25.3 fat powder 18.2 Coffee whitener, foaming 28.0 Hydrocolloids / emulsifiers 1.8 lactose 4.7 Semifinished product B from application example 1 6.0

ANWENDUNGBEISPIEL 6APPLICATION EXAMPLE 6 Teegetränktea beverage

Der Tee und die Halbfertigware werden gemischt und in Teebeutel aus Filterpapier abgepackt. Zur Anwendung wird ein Teebeutel in 100 - 250 ml kochendes Wasser aufgegossen und 2 - 5 min ziehen gelassen. Tabelle 8 Zusammensetzung Teegetränk - Mengenangaben als Gew.-% Zubereitung A grüner Tee, China, Blattware 91,90 Halbfertigware B aus Anwendungsbeispiel 2 8,0 Aroma (Typ Zitrone) 0,1 The tea and semi-finished goods are mixed and packaged in teabags made of filter paper. For application, a tea bag is poured into 100 - 250 ml of boiling water and left for 2 - 5 min. <b> Table 8 </ b> Tea beverage composition - amounts in% by weight preparation A green tea, China, leaf products 91,90 Semifinished product B from application example 2 8.0 Aroma (type lemon) 0.1

ANWENDUNGSBEISPIEL 7APPLICATION EXAMPLE 7 Verwendung in einer bitteren SchokoladeUse in a bitter chocolate

Eine bittere Schokolade wurde aus folgenden Rohstoffen hergestellt und anschließend in rechteckigen Formen ausgegossen. Tabelle 9 Zusammensetzung Schokolade - Mengenangaben als Gew.-% Zubereitung A Kakaomasse 55,55 Kakaobutter 11,70 Zucker 29,50 Magermilch 3,00 Lezithin 0,2 Vanillin 0,035 Homoeriodictyol 10 % in Ethanol 0,05 A bitter chocolate was made from the following raw materials and then poured into rectangular molds. <b> Table 9 </ b> Composition of chocolate - amounts in% by weight preparation A cocoa paste 55.55 cocoa butter 11,70 sugar 29,50 skimmed milk 3.00 lecithin 0.2 vanillin 0,035 Homoeriodictyol 10% in ethanol 0.05

ANWENDUNGSBEISPIEL 8APPLICATION EXAMPLE 8 Zuckerfreie HartkaramelleSugar-free hard caramel

Palatinit wurde mit Wasser gemischt und die Mischung bei 165 °C aufgeschmolzen und anschließend auf 115°C abgekühlt. Die übrigen Bestandteile wurden zugegeben und nach dem Durchmischen in Formen gegossen, nach dem Erstarren aus den Formen entfernt und anschließend einzeln verpackt. Tabelle 10 Zusammensetzung Karamelle - Mengenangaben als Gew.-% Zubereitung A B C Palatinit, Typ M 75,00 74,00 75,00 Zitronensäure - 1,0 - Wasser 24,88 24,842 24,844 Farbstoff gelb - 0,01 - Farbstoff blau 0,01 - 0,01 Pfefferminzaroma 0,1 - 0,1 Zitronenaroma - 0,1 - Rebaudiosid A 98 % - 0,040 0,040 Hesperetin - 0,001 0,001 Phloretin - 0,002 - Homoeriodictyol 0,010 0,005 0,005 Matairesinol - 0,005 - Enterolacton - - 0,005 Palatinit was mixed with water and the mixture was melted at 165 ° C and then cooled to 115 ° C. The remaining ingredients were added and poured into molds after mixing, removed from the molds after solidification and then individually packaged. <b> Table 10 </ b> Caramel composition - by weight as% by weight preparation A B C Palatinit, type M. 75.00 74,00 75.00 citric acid - 1.0 - water 24.88 24.842 24.844 Yellow dye - 0.01 - Dye blue 0.01 - 0.01 Minty 0.1 - 0.1 lemon flavor - 0.1 - Rebaudioside A 98% - 0,040 0,040 hesperetin - 0.001 0.001 phloretin - 0,002 - homoeriodictyol 0,010 0.005 0.005 matairesinol - 0.005 - enterolactone - - 0.005

Claims (7)

  1. A pharmaceutical preparation, comprising
    bitter-masking acting hydroxyflavones selected from the group consisting of eriodictiyol-7-methylether, homoeridictyol, and their sodium-, potassium-, calcium-, magnesium- or zinc salts (component a)
    for use for reducing and/or inhibiting gastric acid secretion induced by food constituents (component b),
    selected from the group consisting of xanthine, fruit acids, phenolic glycosides, flavone glycosides, dihydrochalcone glycosides, hydrolyzable and non-hydrolyzable tannins and oligomers thereof, terpenoid or iridoid bitter substances and triterpene glycosides and mixtures thereof.
  2. Preparations for use according to claim 1, characterized in that said food constituents inducing gastric acid secretion are selected from the group consisting of caffeine, theobromine, theophylline, tartaric acid, racemic acid, malic acid, succinic acid, salicin, arbutin, neohesperidin, eriocitrin, neoeriocitrin, narirutin, naringin, phloridzin, trilobatin, gallic and ellagic esters of carbohydrates, galloylated catechins and epicatechins and oligomers thereof, proanthocyanidins, procyanidins, thearubigin, quercetin, quercitrin, rutin, taxifolin, myricetin, myricitrin, limonin, nomilin, lupolone, humolone, steviosides, rubodid, stevioside, rebaudioside A, rebaudioside C, glycyrrhizin, glycyrrhetic acid and oleuropein and mixtures thereof.
  3. Pharmaceutical preparations for use according to at least one of claims 1 to 2, characterized in that said preparations comprise each of components (a) and (b) in amounts of from 0.1 to 1.000 ppm.
  4. Pharmaceutical preparations for use according to at least one of claims 1 to 3, characterized in that said preparations comprise each of components (a) and (b) in amounts of from 3 to 300 ppm.
  5. Preparations for oral consumption, comprising
    (a) bitter-masking acting hydroxyflavones selected from the group consisting of eriodictiyol-7-methylether, homoeridictyol, and their sodium-, potassium-, calcium-, magnesium- or zinc salts (component a), and
    (b) compounds, which induce gastric acid secretion, selected from the group consisting of xanthine, fruit acids, phenolic glycosides, flavone glycosides, dihydrochalcone glycosides, hydrolyzable and non-hydrolyzable tannins and oligomers thereof, terpenoid or iridoid bitter substances and triterpene glycosides and mixtures thereof (component b),
    characterized in that said preparations comprise each of components (a) and (b) in amounts of from 3 to 300 ppm.
  6. Preparation according to claim 5, characterized in that said preparation is in the form of bakery products, confectionery, alcoholic or non-alcoholic drinks, meat products, eggs or egg products, cereal products, milk products, products made from soy protein or other soybean fractions, fruit preparations, vegetable preparations, snack foods, products based on fat and oil or emulsions of the same, other ready meals and soups, spices, spice mixtures and seasonings.
  7. Preparation according to claim 5, characterized in that said food constituents inducing gastric acid secretion are selected from the group consisting of caffeine, theobromine, theophylline, tartaric acid, racemic acid, malic acid, succinic acid, salicin, arbutin, neohesperidin, eriocitrin, neoeriocitrin, narirutin, naringin, phloridzin, trilobatin, gallic and ellagic esters of carbohydrates, galloylated catechins and epicatechins and oligomers thereof, proanthocyanidins, procyanidins, thearubigin, quercetin, quercitrin, rutin, taxifolin, myricetin, myricitrin, limonin, nomilin, lupolone, humolone, steviosides, rubodid, stevioside, rebaudioside A, rebaudioside C, glycyrrhizin, glycyrrhetic acid and oleuropein and mixtures thereof.
EP13151578.5A 2013-01-17 2013-01-17 Pharmaceutical compositions Active EP2756765B1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP13151578.5A EP2756765B1 (en) 2013-01-17 2013-01-17 Pharmaceutical compositions
US14/761,474 US10226445B2 (en) 2013-01-17 2014-01-15 Pharmaceutical preparations
PCT/EP2014/050742 WO2014111436A1 (en) 2013-01-17 2014-01-15 Pharmaceutical preparations
PCT/EP2014/050950 WO2014111546A1 (en) 2013-01-17 2014-01-17 Method for the identification of bitter tasting compounds and bitter taste modulating compounds
EP14702464.0A EP2946208A1 (en) 2013-01-17 2014-01-17 Method for the identification of bitter tasting compounds and bitter taste modulating compounds
US14/761,804 US20150362481A1 (en) 2013-01-17 2014-01-17 Method for the identification of bitter tasting compounds and bitter taste modulating compounds
US16/248,921 US20190216770A1 (en) 2013-01-17 2019-01-16 Pharmaceutical preparations
US17/339,183 US20210330641A1 (en) 2013-01-17 2021-06-04 Pharmaceutical Preparations

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP13151578.5A EP2756765B1 (en) 2013-01-17 2013-01-17 Pharmaceutical compositions

Publications (2)

Publication Number Publication Date
EP2756765A1 EP2756765A1 (en) 2014-07-23
EP2756765B1 true EP2756765B1 (en) 2019-03-27

Family

ID=47628003

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13151578.5A Active EP2756765B1 (en) 2013-01-17 2013-01-17 Pharmaceutical compositions

Country Status (3)

Country Link
US (3) US10226445B2 (en)
EP (1) EP2756765B1 (en)
WO (1) WO2014111436A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3235492B1 (en) 2016-04-20 2019-06-12 Symrise AG Use of homoeriodictyol (hed) for reducing the gastric acid secretion stimulating effect of n-acetyl-4-aminophenol (paracetamol)
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
CN109588568B (en) * 2018-12-18 2022-04-08 南京农业大学 Method for improving reproductive performance of sows by adding procyanidine into daily ration
WO2023016630A1 (en) * 2021-08-10 2023-02-16 Symrise Ag Flavoring compositions for taste improvement

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1258200A2 (en) * 2001-05-11 2002-11-20 Haarmann & Reimer Gmbh Use of hydroxyflavones for masking of bitterness, and food and pharmaceutical compositions comprising an effective amount thereof

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3603576A1 (en) * 1986-02-06 1987-08-13 Code Kaffee Handel USE OF TANNING SUBSTANCES AND / OR CHLOROIC ACID AND FOOD, ENJOYMENT AND / OR MEDICINAL PRODUCTS WITH ADDITIVES OF TANNING AGENT AND / OR CHLOROGENIC ACID
DE69109114T2 (en) * 1991-09-23 1995-09-28 Kraft Foods Inc Decaffeinated coffee products with a reduced potassium content.
US20020106388A1 (en) * 2000-11-24 2002-08-08 Pugliese Peter T. Formulation of flavones and isoflavones for treatment of cellulite
DE60213957T2 (en) * 2001-04-04 2007-03-08 Unilever N.V. USE OF LIGNAN IN FOOD PRODUCTS
EP1709958A1 (en) 2002-12-05 2006-10-11 Symrise GmbH & Co. KG Seamless filled capsules
DE102004017076A1 (en) 2004-04-07 2005-10-27 Symrise Gmbh & Co. Kg Use of gamma-aminobutyric acid for masking or reducing an unpleasant taste impression and preparations containing gamma-aminobutyric acid
DE102004041496A1 (en) 2004-08-27 2006-03-02 Symrise Gmbh & Co. Kg Hydroxybenzoic acid amides and their use for masking bitter taste
WO2007003527A1 (en) 2005-07-05 2007-01-11 Symrise Gmbh & Co. Kg Hydroxyphenylalkadiones and their use for masking bitter taste and/or for intensifying sweet taste
EP2368442B1 (en) 2005-07-27 2014-12-17 Symrise AG Use of hesperetin for enhancing the sweet taste
US8778987B2 (en) * 2007-03-13 2014-07-15 Symrise Ag Use of 4-hydroxychalcone derivatives for masking an unpleasant taste
EP2220945B1 (en) * 2008-12-11 2013-03-27 Symrise AG Aroma composition to reduce or suppress undesirable bitter and astringent taste impressions of sweeteners
US20100292175A1 (en) * 2009-05-15 2010-11-18 Leibniz-Institut fur Pflanzenbiochemie Use of hydroxyflavan derivatives for taste modification
ES2389709T3 (en) * 2010-02-01 2012-10-30 Symrise Ag Use of 1- (2,4-dihydroxyphenyl) -3- (3-hydroxy-4-methoxyphenyl) -propan-1-one
EP2517574B1 (en) 2011-04-29 2015-11-11 Symrise AG Specific vanillyl lignanes and their use as taste enhancers
EP2570035B1 (en) * 2011-09-15 2014-06-18 Symrise AG Use of neoflavanoids for modifying taste
EP2730178B1 (en) * 2012-11-12 2020-08-26 Symrise AG Oral compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1258200A2 (en) * 2001-05-11 2002-11-20 Haarmann & Reimer Gmbh Use of hydroxyflavones for masking of bitterness, and food and pharmaceutical compositions comprising an effective amount thereof

Also Published As

Publication number Publication date
US20160081977A1 (en) 2016-03-24
EP2756765A1 (en) 2014-07-23
WO2014111436A1 (en) 2014-07-24
US20210330641A1 (en) 2021-10-28
US20190216770A1 (en) 2019-07-18
US10226445B2 (en) 2019-03-12

Similar Documents

Publication Publication Date Title
EP2298084B1 (en) Sweetener-reduced products, aromatic mixtures for same and method of producing such products
EP2517574B1 (en) Specific vanillyl lignanes and their use as taste enhancers
EP2386211B1 (en) Use of rubusoside to reduce or suppress particular unpleasant taste sensations
EP2353403B1 (en) Use of 1-(2,4-dihydroxy-phenyl)-3-(3-hydroxy-4-methoxy-phenyl)-propan-1-on
EP2058297B1 (en) Use of alkamides for masking an unpleasant flavor
EP2008530B1 (en) Aroma composition for reducing or suppressing unwanted bitter and astringent impressions
EP2253226B1 (en) Use of hydroxyflavone derivatives for modifying taste
JP6954915B2 (en) Use of 3- (3-Hydroxy-4-methoxy-phenyl) -1- (2,4,6-trihydroxy-phenyl) -propane-1-one
US20210330641A1 (en) Pharmaceutical Preparations
EP2730178B1 (en) Oral compositions
EP2597082A1 (en) Compounds for masking an unpleasant taste
EP2559346A1 (en) Oleanene-type triterpene glycosides as masking agents
EP2725026B1 (en) Heterocyclic neoflavonoids with taste masking properties
EP2135616B1 (en) Dried bilberries for influencing intestinal conditions
EP2767174B1 (en) Oral compositions
DE102012214560A1 (en) Use of 1-3 enterodiol compounds comprising e.g. (2R,3S)-2,3-bis-(3-hydroxy-benzyl)-butane-1,4-diol for sensorially changing unpleasant taste impression, preferably bitter-, astringent- and/or metallic taste impression of bitter substance
DE102009046126A1 (en) Orally consumable preparation, useful e.g. in cosmetic preparation e.g. lipstick and as baked goods, comprises naturally occurring sweet-tasting substances and a root extract of Mondia whitei containing 2-hydroxy-4-methoxybenzaldehyde
JP6679845B2 (en) Beverage
WO2016169869A1 (en) Preparations with dehydroabietic acid
CN102497787A (en) Improvements in or relating to organic compounds
JP2010184886A (en) New compound
DE602004001519T2 (en) COMPOSITIONS OF NATURAL PRODUCTS AND USE THEREOF
JP3203572B2 (en) Method for improving palatability of pine extract and oral intake obtained by this method
EP4082540A1 (en) Novel use of steviol
JP2024023667A (en) Liver function improver

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130117

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

R17P Request for examination filed (corrected)

Effective date: 20150120

RBV Designated contracting states (corrected)

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

17Q First examination report despatched

Effective date: 20160601

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 502013012471

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A23L0001300000

Ipc: A23F0003400000

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 47/22 20060101ALI20180618BHEP

Ipc: C07K 14/705 20060101ALN20180618BHEP

Ipc: A23F 5/46 20060101ALI20180618BHEP

Ipc: A23L 2/52 20060101ALI20180618BHEP

Ipc: A61K 31/353 20060101ALI20180618BHEP

Ipc: A61K 9/68 20060101ALI20180618BHEP

Ipc: A61K 9/00 20060101ALI20180618BHEP

Ipc: A61K 31/341 20060101ALI20180618BHEP

Ipc: A23L 33/10 20160101ALI20180618BHEP

Ipc: A23F 3/40 20060101AFI20180618BHEP

Ipc: A61K 9/19 20060101ALI20180618BHEP

Ipc: A61K 9/48 20060101ALI20180618BHEP

Ipc: A23L 27/00 20160101ALI20180618BHEP

Ipc: A61K 31/365 20060101ALI20180618BHEP

Ipc: G01N 33/50 20060101ALN20180618BHEP

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20180730

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1111908

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190415

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 502013012471

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190627

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20190327

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190627

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190628

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190727

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190727

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 502013012471

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

26N No opposition filed

Effective date: 20200103

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20200131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200117

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200131

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200131

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200131

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200117

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 1111908

Country of ref document: AT

Kind code of ref document: T

Effective date: 20200117

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200117

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20190327

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240119

Year of fee payment: 12

Ref country code: GB

Payment date: 20240124

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20240124

Year of fee payment: 12